Marginal Zone Lymphomas

L. Jeffrey Medeiros, MD MD Anderson Cancer Center Indolent B-Cell Lymphomas in WHO Classification

Lymphoma Type Frequency 29 % Small lymphocytic lymphoma/CLL 12 % Extranodal MZL/MALT lymphoma 9 % Nodal marginal zone lymphoma 2 % Lymphoplasmacytic lymphoma/WM 1.4 % Splenic marginal zone lymphoma 0.9 %

WHO book, p. 164 What do normal MZ do?

First line of defense against foreign organisms T-cell independent Bulk of primary antibody response

Short-lived antibody production No memory B-cells are not generated

Extranodal MZL/MALT Lymphoma First Description

Malignant Lymphoma of Mucosa-Associated Lymphoid Tissue

A Distinctive Type of B-Cell Lymphoma

PETER ISAACSON, DM, MRC PATH, AND DENNIS H. WRIGHT, MD, FRC PATH As illustrated in the two cases described in this paper close morphologic and immunohistochemical similarities exist between Mediterranean lymphoma (MTL) and primary gastrointestinal lymphoma of follicle center (FCC) origin as it occurs in Western countries. Similarities between the two conditions include a dense noninvasive monotypic lamina propria plasma cell infiltrate, present in all cases of MTL and in some cases of Western gastrointestinal FCC lymphoma, and an invasive infiltrate of FCCs morphologically distinct from the plasma cells. A distinctive lesion produced by individual gland invasion characterizes both types of lymphoma. A clonal relationship between the lamina propria plasma cells and the invasive FCCs, long suspected but never proved in MTL, can be demonstrated in Western cases. Many of the histologic and clinical features common to these lymphomas can be explained in the context of the normal maturation sequences of gut associated lymphoid tissue. It is suggested that MTL and Western cases of primary FCC gastrointestinal lymphoma share a common histogenesis from mucosa associated lymphoid tissue.

Peter Isaacson Cancer 52: 1410, 1983 Dennis Wright Extranodal Marginal Zone Lymphoma of Mucosa- associated Lymphoid Tissue (MALT Lymphoma) Definition

An extranodal lymphoma composed of morphologically heterogeneous small B-cells including marginal zone cells, monocytoid cells, small lymphocytes and scattered immunoblasts and centroblast-like cells. There is plasmacytoid differentiation in a proportion of cases. The infiltrate is in the marginal zone of reactive B-cell follicles… In epithelial tissues lymphoepithelial lesions can be present.

WHO book, p. 214 MALT Lymphoma Clinical Findings

EMZL FL

Median age 60 yrs 59 yrs Male 48 % 42 % BM+ 14 % 42 % B symptoms 19 % 28 % Stage I-II 67 % 33 % III-IV 33 % 67 %

Blood 89: 3909, 1997 MALT Lymphoma Freedom from progression

Follicular Lymphoma at MDACC Blood 95:802, 2000 MALT Lymphomas Relative Frequency of Involved Sites

Stomach 28 % Skin 20 % Salivary gland 17 % Ocular adnexae 15 % Intestine 6 % Lung 6 % Thyroid gland 2 % Breast 2 % Liver 2 % Other 2 %

Leukemia 18: 1722, 2004 MALT Lymphoma Unusual Sites

Almost any site can be involved Dura Tongue gland Pleura Muscle Gallbladder Kidney Cervix Endometrium Ovary Testis

MALT Lymphoma and Ileum Uncommon sites for MALT lymphoma These sites have abundant MALT tissue Many lymphoepithelial lesions

Tonsils Usually we receive bigger specimens Can assess architecture

Ileum Tiny endoscopic biopsy specimens No architecture to assess I cannot diagnose MALT lymphoma H . pylori MALT Lymphoma of Skin Immunocytoma Pattern

Kappa CD20

Kappa Lambda MALT Lymphoma of Conjunctiva Plasmacytoid Differentiation Can be Prominent

PAS Dutcher bodies = nuclear pseudoinclusions of cytoplasm Numerous Dutcher bodies support lymphoma MALT Lymphomas Histologic Features

Neoplastic small lymphoid cells

Small round lymphocytes Monocytoid cells Centrocyte-like cells Plasmacytoid lymphocytes

Occasional large cells (blasts)

Lymphoepithelial lesions

Reactive follicles MALT Lymphoma of Stomach Follicular Colonization

This case was CD10-, BCL6-, and t(14;18)- MALT Lymphoma in Regional

20% of pts have regional LNs at dx

Little impact on prognosis MALT Lymphoma Can be Multicentric

Stomach Lung ~ 25% of pts May not be clonally related (true in this case) MALT Lymphoma Associated Infections and Autoimmune Diseases

Stomach Helicobacter pylori Skin Borrelia burgdorferi (Europe) Jejunum Campylobacter jejuni Ocular adnexa Chlamydia psittaci Lung Achromobacter xylosoxidans Lymphoid interstital pneumonia Thyroid Hashimoto thyroiditis Salivary gland Sjogren syndrome

Hepatitis C may have a role for non-gastric cases (Italy) Pathogenesis of MALT Lymphoma

Infection Autoimmune

Antigen

Chronic inflammation

Organized MALT tissue

B-cell clones emerge Genetic Hits MALT lymphoma More Genetic 3-18% of pts Hits DLBCL MALT Lymphoma Immunophenotype

Positive Negative Immunoglobulin CD3, CD5 CD19, CD20, CD22, CD10 CD79A, PAX5 BCL2 CD23 -/+

IRTA* BCL6

MNDA* Cyclin D1

* Less than 100% sensitive CLONALITY IN MALT LYMPHOMA Sensitivity of detection depends on method

Method Sensitivity Comment Paraffin IHC ~10% Need plasmacytoid (kappa, lymphocytes/plasma lambda) cells

Flow ~ 0.1-001% % clonal cells cytometry important PCR IGH ~ 0.1% Many false negatives

Size of clone important

Chromosomal Translocations in MALT Lymphoma The Famous 4

Abnormality Genes Frequency t(11;18)(q21;q21) API2 (BIRC3) 20-30% and MALT1 t(14;18)(q32;q21) IGH and MALT1 10-15% t(3;14)(p14.1;q32) FOXP1 and ~10% MALT1 t(1;14)(p22;q32) BCL10 and IGH ~5% Cytogenetic/Molecular Abnormalities in MALT Lymphoma

Abnormality Genes Frequency 3q27/BCL6 BCL6 <5% rearrangements t(X;14)(p11.2;q32) GPR34 and IGH 2-3%

t(1;2)(p22;p12) BCL10 and IGK ~1% t(1;14) CNN3 and IGH Rare t(5;14)(q34;q32) ODZ2 and IGH Rare t(9;14)(p24;q32) JMJD2C and IGH Rare t(6;7)(q25;q11) Unknown Rare Del(6p23) TNFAIP3/A20 10-20%

Trisomy 3 and 18 Unknown 40-60% Trisomy 7 and 12 Unknown ~30% MALT Lymphomas Translocation Frequency Related to Site

Site t(11;18) t(14;18) t(1;14) Stomach 24 % 1 % 0 % Skin 8 % 14 % 0 % Salivary gland 2 % 12 % 2 % Ocular 3 % 24 % 0 % adnexae Intestine 13 % 0 % 12 % Lung 53 % 7 % 7 %

Leukemia 18: 1722, 2004 MALT Lymphoma Common Activation of NF-kB pathway

Nat Rev Cancer 4: 644, 2004 MALT-Lymphoma of Stomach Clinical Implications of t(11;18) t(11;18) +

Poorer response to antibiotics for H. pylori Higher stage Often do not progress to large cell lymphoma t(11;18) -

Usually respond to antibiotic therapy Lower stage May progress to large cell lymphoma Clues to Diagnosis of MALT Lymphoma

Extranodal site History of infection or autoimmune disease Monocytoid or plasmacytoid lymphocytes Dutcher bodies (many) Too many B-cells by IHC Appropriate immunophenotype CD20+, CD5-, CD10-, BCL6-, cyclin D1-

Warning: systemic B-cell lymphomas can initially present in an extranodal site – need to exclude Nodal Marginal Zone B-cell Lymphoma Definition

A primary nodal B-cell neoplasm that morphologically resembles lymph nodes involved by MZL of extranodal or splenic types but without evidence of extranodal or splenic disease

Old name: monocytoid B-cell lymphoma

WHO book, p. 218 Nodal Marginal Zone Lymphoma Clinical Findings

NMZL FL

Age 58 y 59 y Male 42 % 42 % BM+ 32 % 42 % B symptoms 37 % 28 % Stage I-II 26 % 33 % III-IV 74 % 67 %

Blood 89: 3909, 1997 Nodal Marginal Zone Lymphoma

Survival

Overall Failure-Free

J Clin Oncol 17: 2486, 1999 Nodal Marginal Zone Lymphoma Histologic Features

Marginal zone distribution Abundant cytoplasm Often pale at low power Plasmacytoid differentiation +/- Follicular colonization +/- Nodal Marginal Zone Lymphoma Marginal Zone Pattern and Pale Cytoplasm Nodal Marginal Zone Lymphoma Marginal Zone Pattern and Clear Cytoplasm

Nodal Marginal Zone Lymphoma Cytologic Spectrum

Monocytoid Plasmacytoid Nodal Marginal Zone Lymphoma Hint of Residual Germinal Centers

BCL2 Ki67 Nodal Marginal Zone Lymphoma Follicular Colonization

Nodal Marginal Zone Lymphoma Can do by FNA with Flow/Ipox Fine Needle Aspiration of LN - Components

Smears

Ipox

Flow Imprint

Clot Nodal Marginal Zone Lymphoma

Immunophenotype

Ipox CD19, CD20, PAX5, BCL2

Flow CD11c+/- CD23-/+ CD25-/+ FMC7+/- CD5- ,CD10- Molecular Features

No characteristic translocations Hum Pathol 45: 1730, 2014 Diagnosis MNDA Positive NMZL 16 / 24 (66.7%) EMZL 27 / 44 (61.4%)

SMZL 5 / 21 (23.8%) CLL/SLL 4 / 31 (12.9%) MCL 9 / 140 (6.4%) LPL 2 / 8 (25.0%) FL 6 / 110 (5.5%) DLBCL 2 / 61 (3.3 %) Immunoglobulin superfamily receptor translocation-associated 1

EMZL 307/329 (93%) NMZL 154/210 (73%) SMZL 0/21 (0%) DLBCL 69/256 (27%)

All other B- and T-NHLs are negative for IRTA1

Histopathology 61: 930, 2012 KMT2D 34% PTPRD 20% NOTCH 20% KLF2 17%

PTPRD mutations are unique to nodal MZL Blood 128: 1362, 2016 Differential Diagnosis of Nodal MZL

Other types of MZL Usually not too difficult because there are extranodal sites or

Lymphoplasmacytic lymphoma/Waldenstrom

Follicular Lymphoma

Lymphoplasmacytic Lymphoma/ Waldenstrom Macroglobulinemia Nodal MZL versus LPL/WM

Feature Nodal MZL LPL/WM Serum IgM ~ 5-10% pts 100% of WM

Bone marrow + 30-40% of pats 100%

Distribution Cortical Medullary

Sinuses Often effaced Usually patent

Follicles Large, reactive Usually small

Cell cytoplasm Pale (monocytoid) Darker (purple)

Dutcher bodies Uncommon Common

IRTA1, MNDA +/- Negative

MYD88 L265P Very rare >90% Nodal Marginal Zone Lymphoma Can Colonize Follicles and mimic FL

Ki67 CD10 BCL2 Nodal MZL with Follicular Colonization versus FL

Feature Nodal MZL Follicular Lymphoma Distribution of Confined to lymph node Extend into perinodal fat follicles Growth Tumor begins outside Tumor begins in follicle pattern follicle and grows in and grows out Cytology Often rounder cells Centrocytes/centroblasts +/- plasm differentiation Plasm diff is rare Cell cytoplasm Pale (pink) Darker (blue) CD10/BCL6 Germinal centers+ +/- Tumor cells- BCL-2 Germinal centers - +/- Tumor cells+ Ki-67 Germinal centers high Usually low Tumor low (unless grade 3 FL) IGH-BCL2 Absent Present Follicular Lymphoma vs Nodal MZL

IRTA1 MNDA CD10 BCL-6 LMO2 HGAL

Brand and Van Krieken, Haematologica 100: e359, 2015 Nodal MZL versus Follicular Lymphoma Does It Matter Clinically?

Patients with FL have Higher stage More frequent BM + More abdominal LNs + More frequent transformation to DLBCL

FL usually transforms to DLBCL of GCB type NMZL usually transforms to DLBCL of non-GCB type

May not matter much for patient at diagnosis Few therapeutic implications Does have prognostic meaning

Leuk Lymphoma 57: 1649, 2016 Clues to Diagnosis of Nodal MZL

No extranodal sites of disease Adundant pale cytoplasm Marginal zone distribution Dutcher bodies (many) Appropriate B-cell immunophenotype CD20+, CD5-, CD10-, BCL6-, cyclin D1- IRTA1+ and MDNA+

NMZL is often a diagnosis of exclusion

There is overlap with lymphoplasmacytic lymphoma Splenic Marginal Zone Lymphoma Clinical Features

Median Age 65 years

Symptoms Fatigue Abdominal discomfort May be asymptomatic

Laboratory 33 % paraprotein 10% autoimmune phenomena ? association with hepatitis C

Splenic Marginal Zone Lymphoma Characteristic Disease Distribution

Spleen and hilar lymph nodes Abdominal lymph nodes (80-90%) Peripheral blood ± Liver ± Splenic Marginal Zone Lymphoma Pathologic Findings Spleen Usually massive Red and ± Plasmacytoid differentiation

Bone marrow Paratrabecular and non-paratrabecular ± Germinal centers ± Intrasinusoidal (~33%)

Peripheral blood ± Villous lymphocytes Splenic Marginal Zone Lymphoma Spleen Splenic Marginal Zone Lymphoma Spleen Splenic Marginal Zone Lymphoma Splenic

Partial

Extensive Splenic Marginal Zone Lymphoma Cytologic Features Splenic Marginal Zone Lymphoma Spleen

CD20 Splenic Marginal Zone Lymphoma Splenic White Pulp

BCL2 CD21 Splenic Marginal Zone Lymphoma Lymph Node Splenic Marginal Zone Lymphoma Liver – 2 Examples

Sinusoidal Extensive Splenic Marginal Zone Lymphoma Peripheral Blood Smear Splenic Marginal Zone Lymphoma Immunophenotype Ipox CD20+, PAX5+, BCL2+, annexin A1-

Flow sIg+ (bright), IgM+, IgD+ (most) CD11c+, CD5 -/+, CD23 -/+, CD10-, CD25-

Cytogenetics Deletion 7q/7q31-32 40-50 % Trisomy 3 15-35 %

Molecular Biased use of IgH variable genes (IgHV1-2) Splenic Marginal Zone Lymphoma Common Mutations

Blood 127: 2072, 2016 Splenic Marginal Zone Lymphoma Differential Dx with Other Splenic Lymphomas

SMZL HCL HCL-V SDRPL Age (yrs) 62 55 71 77 M/F 0.5 5 1.6 1.6 Lymphocytosis +/-Moderate No High Moderate Monocytopenia No Severe No No Survival (yrs) 10 12 9 10 Pattern White pulp Red pulp Red pulp Red pulp

Nucleolus Small No Moderate or large Large +/- CD25 Variable Bright Dim or Neg Dim CD103 Neg Bright ~ 60% dim 30%

Cyclin D3 Neg Neg Neg Positive

Annexin A1 Neg Positive Neg Neg BRAF Neg Positive Neg (MAP2K1) Neg Can We Diagnose MZL by Bone Marrow Only?

CD21

MZLs in bone marrow are usually associated with follicular dendritic cells (CD21+ and/or CD23+)

Extranodal and nodal MZL are indistinguishable

Splenic Marginal Zone Lymphoma Bone Marrow

CD20

Support for SMZL Frequency GCs 10% Sinusoidal pattern 33% CBC abnormalities 70% Criteria for large cell transformation in MZL?

NMZL

DLBCL

16 months later

Sheets of large cells are best and perhaps only criterion Otherwise be conservative Ki67 and p53 can be helpful